This proposal aims to apply recent advances in the understanding of BRCA1 and BRCA2 function to the clinical problem of uncharacterized variant alleles of BRCA1 and BRCA2. As more women have their BRCA1 and BRCA2 genes sequenced, distinguishing between true- disease causing alleles and benign polymorphisms has become a critical clinical issue. At present, no assay exists that reflects the tumor suppression activity of these genes. In Specific Aim 1 we propose to develop an assay based on the ability of various alleles to complement defects in radiation resistance and DNA double strand break repair in a BRCA1-BRCA2 demonstrate the haploinsufficiency. If this is the case, we will investigate the possibility that any much phenotype could form the basis for an assay aimed at distinguishing benign from disease-linked alleles of BRCA1 and BRCA2.